Wilms' tumor (WT) is an embryonal malignancy of the kidney which affects approximately 1 in 10,000 infants and young children. Matsunaga, Human Genetics, 57:231-246 (1981). The molecular basis of Wilms' tumor is not well understood.
The majority of WTs are sporadic tumors (>95%). A small set of WTs occur in a hereditary setting as familial cases or as part of cogential disorders such as the WAGR syndrome. Wilms' tumor (W) cases (approximately 2%) can occur in association with aniridia (A), a defect in the development of the iris, as well as genitourinary (G) abnormalities and mental retardation (R). Miller et al., New Engl. J. Med., 270:922-927 (1964). These disorders form the WAGR syndrome, and can be attributed to a constitutional deletion of DNA in band 11p13 on human chromosome 11 in a group of genes known as the WAGR complex. Riccardi, et al., Pediatrics, 61:604-610 (1978); Francke, et al., Cytogenet. Cell Genet., 24:185-192 (1979). In these cases, bilateral Wilms' tumors are frequently observed, as are dysplastic changes in surrounding renal tissue (nephroblastomatosis) which are thought to precede malignant transformation (i.e., precancerous conditions). Bove and McAdams, Perspectives on Pediatric Pathol., 3:185-223 (1976). As a recessive oncogene or anti-oncogene, the Wilms' tumor locus is thought to curtail the growth of undifferentiated nephrotic cells. The genetics of WT generally conform to the two-hit mutational model of carcinogenesis used to describe the retinoblastoma locus on chromosome 13q. According to this concept, the rate-limiting events in tumor formation are two mutations. Sporadic tumors develop following two independent events, while familial cases involve transmission of one altered gene in the germline and a somatic mutation in the second gene. Hereditary cases display both a high penetrance and an increased incidence of bilateral cancers, attesting to the frequency of the somatic second event.
Observations have led to the conclusion that at least in a subset of Wilms' tumors, the inactivation of a gene in 11p13, analogous to the retinoblastoma (RB) gene, is a key event in tumor formation. Considerable effort has been expended in attempting to localize the gene responsible for WT, as is evidence by the numerous reports describing such efforts. The localization of a Wilms' tumor gene at 11p13 is supported by the fact that 40-60% of individuals with the WAGR syndrome develop Wilms' tumor.
However, it appears that the genetics of Wilms' tumor are more complex than the two-hit mutational model. Based on additional research, it appears that Wilms' tumor may be caused by loss of function at alternative loci. In studies of two families showing hereditary predisposition to Wilms' tumor, linkage to 11p genetic markers was excluded, indicating the presence of at least one additional Wilms' tumor locus. Grundy, et al., Nature, 336:374-376 (1988); Huff, et al., Nature, 336:377-378 (1988). Further studies showed loss of heterozygosity in Wilms' tumors at 11p15 rather than 11p13. Reeve, et al., Mol. Cell Biol., 9:1799-1803 (1989); Koufos, etal.,Am. J. Hum. Gen., 44:711-719 (1989); Koufos, et al., Nature, 309:170-172 (1984); Orkin, et al., Nature, 309:172-174 (1984); Reeve, et al., Nature, 309:174-176 (1984); Fearon, et al., Nature, 309:176-178 (1984). Although these data suggest the possibility of additional loci, the 11p13 Wilms' tumor locus is clearly associated with constitutional WAGR deletions and somatic chromosome rearrangements in a subset of sporadic tumors. Lewis, etal., Genomics, 3:25-31 (1988).
Despite considerable interest in identifying the Wilms' tumor gene and work focusing on doing so, to the present time, a transcript mapping to the region identified as containing the Wilms' tumor gene has not been identified.